TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling

Abstract

The stromal interaction molecule (STIM)–ORAI calcium release-activated calcium modulator (ORAI) pathway controls store-dependent calcium entry, a major mechanism of physiological calcium signaling in mammalian cells. The core elements of the pathway are the regulatory protein STIM1, located in the endoplasmic reticulum (ER) membrane, the calcium channel ORAI1 in the plasma membrane, and sites of close contact between the ER and the plasma membrane that permit the two proteins to interact. Research on calcium signaling has centered on STIM1, ORAI1, and a few proteins that directly modulate STIM–ORAI function. However, little is known about proteins that organize ER–plasma membrane junctions for STIM–ORAI-dependent calcium signaling. Here, we report that an ER-resident membrane protein identified in a previous genome-wide RNAi screen, transmembrane protein 110 (TMEM110), regulates the long-term maintenance of ER–plasma membrane junctions and the short-term physiological remodeling of the junctions during store-dependent calcium signaling.

The STIM-Orai Pathway: Orai, the Pore-Forming Subunit of the CRAC Channel

“…All of these studies involve overexpression of Orai, however, and they do not establish that overexpressed Orai is gated as efficiently as Orai in the native CRAC channel of T cells and mast cells. In mammalian cells, other associated proteins may modulate the efficiency of CRAC current activation (Srikanth et al 2010; Krapivinsky et al 2011; Palty et al 2012; Jing et al 2015; Sharma et al 2013; Quintana et al 2015; reviewed in Soboloff et al 2012). …”

Orai1 and STIM1 in ER/PM junctions: roles in pancreatic cell function and dysfunction

“…Notably, SARAF interacts with STIM1 only when STIM1 is at the PI(4,5)P 2 -rich ER/PM junctions (62). Interestingly, the interaction between STI-MATE/TMEM110 and STIM1 is Orai1 independent and is concurrent with or precedes STIM1-Orai1 interaction (38,87). Conversely, interaction of SARAF with STIM1 takes place after and indeed requires formation of the STIM1-Orai1 complex (37).…”

“…Accordingly, on store depletion, STIM1 clusters and expands the ER/PM junctions (33). Clustering of STIM1 is regulated by the newly discovered STIM1 interacting protein named STIMATE/TMEM110 (38,87). STIMATE/TMEM110 has ER membrane resident multiple transmembrane domains and a sort cytoplasmic domain that includes a polybasic sequence.…”

“…STIMATE/TMEM110 has ER membrane resident multiple transmembrane domains and a sort cytoplasmic domain that includes a polybasic sequence. STIMATE/TMEM110 interacts with STIM1 to promote its active conformation and stabilizes the STIM1-formed ER/PM junctions (38,87). Deletion of STIMATE/TMEM110 prevents STIM1 clustering and STIM1-Orai1 interaction to inhibit the Orai1 current and Ca 2ϩ influx (38,87).…”

“…STIMATE/TMEM110 interacts with STIM1 to promote its active conformation and stabilizes the STIM1-formed ER/PM junctions (38,87). Deletion of STIMATE/TMEM110 prevents STIM1 clustering and STIM1-Orai1 interaction to inhibit the Orai1 current and Ca 2ϩ influx (38,87). Another protein that regulates STIM1 function is SARAF (75).…”